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Mechanisms and consequences of extrafollicular B cell activation during malaria

疟疾期间滤泡外 B 细胞激活的机制和后果

基本信息

批准号：
10686400
负责人：
Noah Sullivan Butler
金额：
$ 64.71万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686400
关键词：
Acceleration Address Affect Affinity Amino Acid Transporter Amino Acids Antigens Antimalarials B-Cell Activation B-Lymphocytes Biochemical Blood COVID-19 Cell physiology Cells Cellular Metabolic Process Cessation of life Communicable Diseases Data Dengue Detection Development Diet Disease Ebola Environment Epigenetic Process Event Failure Genetic Genetic Transcription Glutamine Goals Human Humoral Immunities Hyperactivity Hypoxia Immune Immune response Immunity Immunologic Memory Immunology Impairment Individual Infection Infectious Disease Immunology Interferons Intervention Knowledge Link Longevity Longitudinal Studies Malaria Mediating Memory B-Lymphocyte Metabolic Metabolism Molecular Mus Nature Nutrient Parasites Pathway interactions Patients Pattern recognition receptor Plasma Cells Plasmablast Plasmodium Population Predisposition Protozoan Infections Reagent Receptor Signaling Reporting Resistance Resolution Shapes Signal Transduction Spleen Structure of germinal center of lymph node Supplementation System Testing Trypanosomiasis imprint improved innovation novel novel strategies nutrient deprivation pathogen plasma cell development programs response single cell technology tool vaccinology

项目摘要

ABSTRACT There is currently a lack of mechanistic understanding of why humoral immunity against malaria is not efficiently induced and why Plasmodium infections are associated immune failures, even following repeated infections. Our long-term goal is to determine how Plasmodium parasites, and potentially other protozoan infections, co-opt and subvert humoral immunity, which will help with the identification and development of new immune-based interventions against devastating diseases like malaria. The objectives of this project are to define mechanisms that trigger initial humoral immune dysregulation and study the consequences of these events on the formation of durable humoral immune memory. Our central hypothesis is that robust humoral immunity does not develop efficiently because polyclonal B cell activation events establish a nutrient sink that impairs the metabolic, transcriptional and epigenetic programming and function of Plasmodium-specific memory B cells. The rationale for this project is linked to our recent discovery that Plasmodium infection results in a massive polyclonal expansion of B cells that function as a nutrient sink that limits protective memory B cell responses. Deletion of these B cells accelerates blood-stage Plasmodium parasite clearance and enhances humoral immune memory. Supplementing the diet of infected mice with a single amino acid is sufficient to overcome the nutrient sink and metabolic constraints imposed by these B cells and results in enhanced humoral immune memory responses. Despite our new findings, the molecular mechanisms governing the activation and function of immunoinhibitory B cells and the impact of these cells on the affinity and longevity of memory B cells remain critical knowledge gaps in our quest to improve humoral immunity against malaria. Two Aims address these priority questions. In the first Aim we will determine the molecular and cellular mechanisms that govern the expansion of these immunosuppressive B cells and investigate whether these populations are relevant to other infections associated with dysregulated humoral immunity. In the second Aim we will investigate the molecular and cellular consequences of immunosuppressive B cell expansions on the genetic and epigenetic programming of memory B cells. We have developed several innovative new reagents that afford unprecedented resolution for the study anti-malarial humoral immunity. The significance of this project is directly linked to our new findings showing that pathophysiological changes that occur during Plasmodium infection durably imprints on B cell fate and function. Thus, determining how these pathways coordinately regulate polyclonal B cell activation, development and humoral immunity will be broadly important to those studying infectious disease immunology and vaccinology.

摘要